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1005-80 Evidence That A3-Receptor Activation Contributes to Preconditioning-induced Cardioprotection in Ischemic Cardiac Myocytes
lACC
ABSTRACfS
February 1995
data support the concept that hemodynamic shear stresses are important in atherogenesis, and that atherosclerotic plaques at arterial bifurcations are more likely to occur in areas believed to be low rather than high-shear.
Preconditioning and Cardioprotection Wednesday, March 22, 1995, Noon-2:00 p,m. Ernest N. Morial Convention Center, Hall E Presentation Hour: 1:00 p.m.-2:00 p.m. Preconditioning with 15-min Ischemia Extends Myocardial Infarct Size After Subsequent 3Q.min Ischemia In Rabbits
11005-761
Kenzo Yamasaki, Hisayoshi FUjiwara 1, RYOli Yokota, Masami Miyamae, Masaru Tanaka. Shigetake Sasayama. Kyoto University, Kyoto, Japan; 1 Gifu University, Gifu, Japan
Ischemic preconditioning (PC) with 5-min ischemia(l) and reperiusion (R) limits infarct size (IS) after subsequent I in rabbits. The aim of this study was to evaluate whether PC with longer I was also protective. Open chest rabbits underwent 30-min occlusion of coronary artery and 48-hrs R. PC was elicited by either a preceding 5-. 10- or 15-min I followed by 5-min R. Additional group underwent 15-min 1& 48-hrs R. IS was measured histologically and expressed as a percentage of the area at risk (MR).
\1005- 78
1
355A
Myocardial Preconditioning by Laser Irradiation
Peter Whittaker, Robert A. Kloner. Heart Institute. Good. Samaritan Hospital & University of Southern California, Los Angeles, CA We previously demonstrated that transmural laser channels made after coronary occlusion did not acutely enhance blood flow or reduce infarct size. In contrast, other studies (which did not measure blood flow) reported increased survival and/or reduction of necrosis when laser channels were made prior to coronary occlusion. To reconcile this apparent paradox. we speculated that laser channels made prior to occlusion might protect the heart via a mechanism independent of blood flow. To test this hypothesis, we randomized 12 rats to either; (1) control: 1 hour of coronary artery occlusion followed by 5 hours of reperiusion. or 12) laser: 6 non-transmural channels were made in the anterior wall of the left ventricle using a holmium:YAG laser coupled to a 400 micron diameter optic fiber. Two minutes after the last channel was made, the left coronary artery was occluded for 1 hour and then reperiused for 5 hours. We monitored lead I of the ECG and noted the incidence of ventricular tachycardia (VT) and fibrillation (VF). At the end of the protocol. the artery was briefly reoccluded and we determined the area at risk (AR) by injection of pigment into the circulation. Heart slices were incubated in triphenyltetrazolium chloride solution to delineate the area of necrosis (AN). which was expressed as a percent of area at risk (AN/AR). [data given as mean ± SEMI
Control Laser
AR
AN/AR
VTNF
49 ± 3 45 ± 5
61 ± 9 35 ± 4*
5 0*
Group
AAR(OfoLV)
IS (%LV)
IS (OfoAAR)
"'p < 0.03 versus control
non-PC (n ~ 15) 5-min PC (n = 10) 10-min PC (n ~ 10) 15-min PC(n = 15) 15-min I (n = 10)
26.7 ± 2.1 26.7 ± 2.7 28.4 ± 31 25.S ± 1.8 2S.3 ± 3.8
11.1 ± 1.5 3.1 ± 1.0* 3.5 ± OS* 20.1 ± 1.S*#b 5.4 ± 1.0*
40.1 ± 38 10.4 ± 2.9* 11.7 ± 24* 77.4 ± 3.7*#b 18.3 ± 1.0*
Although laser channels were associated with thermally-induced necrosis, total infarct size was smaller in laser-treated hearts. Protection of muscle was most prominent in heart slices containing laser channels. but also occurred in slices without channels. Laser treatment also significantly reduced the incidence of VT and VF. In conclusion. non-transmural laser channels "preconditioned" the heart against subsequent ischemia. Although the mechanism of protection is unknown, it cannot be attributed to increased blood flow to the tissue because the channels did not connect to the ventriCUlar cavity.
*p < 0.05 vs. non-PC, #p < 0.05 vs. 5 min PC, b p < 0.05 vs. 10 min PC Since 15-min I caused infarct (18% of AAR). IS caused by test I per se in 15-min PC group was 59.5 ± 3.7% of AAR (p < 0.05 vs. non PC). Thus, PC with 10-min I is as protective as that with 5-min I. However, PC with 15-min I accelerated myocyte necrosis during subsequent I. Conclusion: We conclude that ischemic duration of PC is a determinant of its cardioprotection, and PC with too long ischemia is not protective but harmful.
11005-771
Is Activation of 5' ·Nucleotidase and Following Adenosine Release a Common Pathway for Mediating Ischemic Preconditioning Among Species?
Kazuo Komamura, Masafumi Kitakaze, Koichi Node. Tetsuo Minamino, Yuji Okuyama. Toshinao Kurihara. Yukihiro Koretsune, Michitoshi Inoue. Masatsugu Hori, Takenobu Kamada. The 1st Dept. of Med., Osaka Univ: School of Med.., Osaka, Japan
There is a rising interest on the subcellular mechanism of cardioprotection afforded by ischemic preconditioning (IP). Adenosine has been reported to playa primary role for preconditioning in dogs, pigs. rabbits but not in rats. Common compounds or mechanisms for preconditioning among species would seem to have some benefits in the clinical settings. In dogs. we reported that an increase in ecto-5'-nucleotidase (5'N) activity is responsible for the infarct size (IS)-1imitation of IP To test the hypothesis that IS-limitation afforded by IP is also attributable to activation of 5'N in rabbits, primary branch of the left coronary artery was occluded for 30 min followed by 3 hrs reperfusion with one time occlusion for 5 min prior to prolonged ischemia in the presence or absence of Ct.p-methyleneadenosine 5'-diphosphate (AOPCP). a specific inhibitor of 5'N. In the absence of AOPCP, IS in the IP group was smaller than that in the control group (17.1 ± 1.9 vs. 29.7 ± 5.2% of risk area. mean ± SE. n = 5 each. p < 0.05). although the risk area was not different in both groups. IP increased 5'N activity in ischemic area compared with that in non-ischemic area (42.1 ± 5.0 vs. 21.2 ± 1.9 nmollmg proteinlmin, p < 0.Q1). When non-hypotensive dose of AOPCP (0.3 mg/kg/min) was infused from the left atrium 15 min before the IP and continued for 60 min after reperfusion. IS-limitation was blunted (IS: 30.2 ± 4.7%). Thus we conclude that increase in 5'-nucleotidase activity is primarily responsible for IS-limitation of IP in rabbits. Activation of 5'-nucleotidase may be a commom pathway for mediating IP both in dogs and rabbits.
Serial 1 H NMR Spectroscopic Detection of Myocardial Lipid Accumulation Following Brief Coronary Ischemia and Elevation of Serum Lipids in Dogs James A. Balschi. David D. Ku, Ingrid Straeter-Knowlen, Jenny Hai, Paul Wolkowicz, William 1. Evanochko, Jan den Hollander, James B. Caulfield, Gerald M. Pohost. Div: of Cardiovascular Disease, Department of Medicine, University of Alabama at Birmingham, AL
We employed a 1H NMR surface coil spectroscopic method to continuously monitor myocardial lipid accumulation following 90-min coronary occlusion and 4 hrs reperiusion in 12 dogs. In the 7 saline-treated control dogs, significant myocardial ischemic damage was noted by both triphenyltetrazolium staining and histologic examination. Slight increases (+ 15.5%) in lipid resonances were also observed during 4-hr reperiusion in the reversibly injured subepicardial ischemic/reperfused myocardium, but not the subendo-cardial infarcted region. Transient elevation of serum lipids in 5 dogs from 18 ± 3 mg/dl to 490 ± 182 mg/dl with a 90-min infusion of Intralipid (1 mllkg bolus followed by 0.025 mllkg/min) during reperiusion further increased the lipid resonances in the reversibly injured subepicardium (+61.8%). The subendocardial infarcted tissues were only minimally affected. Discontinuation of Intralipid infusion with return of serum lipids (36 ± 14 mg/dl) did not reverse the myocardial lipid accumulation. Ex vivo determinations of tissue triglyceride content and histochemical (Oil-Red-O) staining confirmed the preferentiallipid accumulation in the reversibly injured myocytes. Conclusion: Results of the present serial 1H NMR spectroscopic study confirm our earlier findings and further suggest a preferential and temporal accumulation of lipids in the ischemically jeopardized myocardium. Increases in serum lipid levels could exacerbate their accumulation in the ischemic myocardium.
11005-80
I
Evidence That A 3 -Receptor Activation Contributes to Preconditioning-induced Cardioprotection In Ischemic Cardiac Myocytes
Jianxun Wang, Lisa Drake, Kevin Mullane, David Bullough. Cardiovascular Research. Gensia Inc., San Diego, CA
Ischemic preconditioning (PC) reduces post-iSChemic myocardial injury by an adenosine-mediated mechanism. This study evaluated the adenosine receptors involved in protecting ischemic cardiac myocytes. Ischemic injury was simulated by exposure of the myocytes (paced at 1 Hz) to ischemic buffer
356A
ABSTRACTS
lACC
containing (mM) 2'-deoxyglucose (20), NaCN (1). Na-lactate (20). K+ (10) at pH o 6.6 (3rC). Changes of myocyte length were monitored with an opticalvideo edge recording system, and hypercontracture was used as the index of irreversible cell injury (cell death). Results: PC (2 min ischemia followed by 15 min reperfusion) significantly reduced cell injury resulting from the subsequentextended ischemia (10 min) and reperfusion (15 min), as indicated bya reduction in cell death from 67 ± 6% (cells ~ 110, control) to 29 ± 5% (cells = 101, with PC, p < 0.001). PC-induced cardioprotection was only partially blocked by the maximally effective dose of the adenosine A, -receptor antagonist DPCPX (1 00 nM) Icell death = 43 ± 3%, cells = 88, P < 0.05 vs control) but completely blocked by either the combination of DPCPX (100 nM) with the adenosine A3-receptor antagonist BW A1433 (1 /LM) (cell death ~ 64 ± 4%; cells = 82; P = NS vs control). or the non-selective adenosine receptor antagonist, 8-SPT (100 /LM) (cell death = 59 ± 5%; cells ~ 86; P = NS vs control). as shown in the Figure. Conclusion: PC-induced cardioprotection is mediated in part through the activation of adenosine A3-receptors.
.-.
80
-
60
C .r: ca GI
•ora
40
"i
20
EJ
o
11005-81 1
Fe PC+OPCPX
~ PC+OPCPX
."
o
control
+ BW A1433 PC+ 8-SPT
Myocardial Protection by Na +IH + Exchange Inhibition in Ischemic, Reperfused Porcine Hearts
Hermann H. Klein, Sibylle Pich, Rainer M. Bohle, Jutta Wollenweber, Klaus Nebendahl. Universities of Marburg and G6ttingen, Fed. Rep. of Germany The protective effect of the Na+/H+ exchange inhibitor HOE 694 was tested in porcine hearts subjected to 45 min of regional ischemia and 24 h of reperfusion. The compound (3 mg/kg) was intravenously injected in 6 pigs each either 10 min before ischemia (group A) or 10 min before reperfusion (group B). Six animals served as controls. Apart from the main end-points, infarct size and regional systolic shortening, the effect of HOE 694 on global hemodynamic parameters which included coronary blood flow and coronary venous oxygen saturation was evaluated. Although the Na+ IH+ exchange inhibitor did not affect global hemodynamics, preischemic treatment with HOE 694 decreased infarct size from 65 ± 18% (control group) to 12 ± 9% (p < 0.01) and improved systolic shortening from 8 ± 6% (control group) to 28 ± 9% P < 0.02). In addition, increase in heart rate and myocardial contracture during early reperfusion were significantly attenuated in group A. Treatment of group B did not exhibit protective effects. Conclusion: Na+/H+ exchange inhibition is a very protective means in myocardial ischemia and reperfusion when administered before ischemia. In this model, it was ineffective when given before reperfusion.
110061
February 1995
Counteracting Thrombin and Lipids in Acute Coronary Syndromes
Wednesday, March 22, 1995, Noon-2:00 p.m. Ernest N. Morial Convention Center, Hall E Presentation Hour: Noon-1 :00 p.m. 11006-41
I
Effect of Previous Treatment with Aspirin or Nitrates on the Clinical Manifestation of Acute Coronary Syndrome
David Garcia-Dorado, Juan Oliveras, Pilar Tornos, Gaieta Permanyer, Antonia Sam bola, Maite Santos, Pierre Theroux, J. Soler-Soler. Hospital Vall d'Hebron, Barcelona, Spain; Montreal Heart Institute, Canada
Aspirin (ASA) and nitrates inhibit platelet aggregation by different mechanisms, and it has been suggested that their antiaggregating effects could be additive. To analyze the influence of previous treatment with aspirin (ASA) or nitrates on the clinical manifestations of acute coronary syndrome, a series of 323 pts consecutively admitted to the cardiology emergency room with unstable angina (UA) or acute myocardial infarction (MI). and with a previous history of coronary heart disease, was prospectively characterized. A standardized questionnaire was used to determine risk factors, previous cardiac history, and use of drugs preceding the index event. Previous use was defined as any dose of ASA during the week before, or of oral or transdermal nitrates during the 24 h before the onset of the event. The final diagnosis by serial ECGs and enzyme determinations, was UA in 226 pts, and MI in 95. Fifty-one pts had received previous treatment with ASA but not with nitrates, 51 had received nitrates but not ASA, 105 had received both drugs and 94 had received neither ASA nor nitrates. The final diagnosis was MI in 12 (24%) pts who had received ASA, 12 (24%) in pts who had received nitrates, 21 (20%) in pts on both ASA and nitrates, and 43 (46%) in those receiving neither ASA nor nitrates (p ~ 0.0003). Multiple logistic regression analysis identified prior ASA and prior nitrates, but not age, sex, risk factors, previous myocardial infarction, or prior treatment with beta blockers or Ca++ entry blockers, as independent predictors of UA vs MI. The regression model did not detect any interaction between ASA and nitrates. These results suggest that both prior treatment with ASA and with nitrates modify the clinical manifestations of acute ischemic syndrome reducing its severity, and that these effects are compatible with their effects being additive.
11006-421
What Beyond Aspirin and Anticoagulation Improves Outcome in Unstable Angina? Effect of Medical Therapy
Steven Borzak, Phillip L. Kraft, Lori Douthat, Christopher P. Cannon, Elliott Antman, Joe Massaro, Sebastian 1. Palmeri, Judith S. Hochman, Carolyn 1. McCabe, Joanna Fuchs, Burt Adelman, TIMI-7 Investigators. Henry Ford Hospital, Detroit, MI; Brigham and Women's Hospital, Boston, MA
11005-821
Myocardial and Coronary Vascular Protection After Coronary Occlusion and Reperfusion by Selective Sinoatrial Node Inhibition
Roger Williams, Wilmer W. Nichols, Liying Chen, Michael S. Stalvey, Linda V. Thompson, Tiffany D. Boyd, Jawahar L. Mehta, Carl J. Pepine. University of Florida and VA Medical Cente" Gainesville, FL
Improved regional myocardial function and abnormal flow reserve resulting from myocardial ischemic injury has been observed with ,II-blockade. To determine if heart rate reduction alone would offer similar protection, anesthetized dogs were subjected to left anterior descending (LAD) occlusion and given a selective SA node inhibitor (ZD7288 0.5 mg/kg, n = 5 or buffer, n = 7). After 1 hour of occlusion they were reperfused. ZD7288 decreased heart rate by 28 ± 2% (153 ± 14 to 120 ± 11 bpm, p < 0.05) at 1 hr after reperfusion. In buffer-treated dogs, peak reactive hyperemic (RH) response after 20 sec LAD occlusion, (index of coronary flow reserve). fell from 276 ± 22% to 135 ± 18% and LAD regional shortening fraction (SF, by ultrasonic crystals) decreased from 9.7 ± 1.5% to 0.6 ± 0.1 % after reperfusion (both, p < 0.001). In ZD7288-treated dogs, peak RH and SF after reperfusion (227 ± 19% and 4.2 ± 0.8%, respectively) were preserved (p < 0.05) vs buffertreated dogs. Despite similar area of left ventricular (LV) at risk, infarct area (as % of LV). was also smaller in ZD7288-treated vs. buffer-treated dogs (14.0 ± 0.5 vs 23.0 ± 1.10%, P < 0.05). Heart rate was maintained constant with atrial pacing in five other ZD7288-treated dogs and neither peak RH or SF were preserved compared with buffer-treated dogs. Thus, selective SA node inhibition alone, induced after coronary occlusion, results in myocardial and coronary vascular protection after reperfusion. Selective SA node inhibition may have clinical utility in acute myocardial patients who are not candidates for beta blockers.
Medical treatment consisting of beta-blockers (BB), calcium blockers (CB) and nitrates (N) is recommended and frequently employed in patients (pts) before and during hospitalization with unstable coronary syndromes (UA). but the benefit is unclear in the setting of combined aspirin and anticoagulation. To study the effect of each of these drugs on in-hospital events, we examined 410 pts with UA entered in the TIMI-7 trial in which all pts received aspirin and one of 4 doses of the direct thrombin inhibitor, hirulog. Prior to hospitalization, 44% of pts received BB, 50% CB, and 51 % N. Compared to pts not on these drugs, pts on each medication were older (average 62 vs 59 yrs). had a higher incidence of prior MI(BB, CB, N), revascularization (CB, N), hypertension (BB, CB, N). and diabetes (CB, N), and were more likely to be receiving aspirin IBB, CB, N). Stepwise regression showed that prior treatment with any of the 3 drugs was not predictive of in-hospital death, MI or documented recurrent ischemia. After enrollment and during hospitalization, 71 % of pts received BB, 66% CB, and 95% N at the discretion of their physicians. The in-hospital occurrence of death (4%). Ml (6%), recurrent ischemia (8%) or their combined incidence (14%), the number or severity of in-hospital anginal episodes, or the incidence of catheterization (64%) or revascularization (38%) were not significantly related to treatment with any of the 3 drugs. The combined incidence of in-hospital death, MI or recurrent ischemia was best predicted by the presence of ECG changes on admission (multivariate adjusted odds ratio [OR] 2.83, p < 0.01) and advanced age (OR 2.38, P < 0.01) but not by other factors. Prior or newly instituted anti-ischemic medical therapy, administered in a nonrandomized fashion in this trial, may have contributed to clinical stability. During hospitalization for UA, aspirin and anticoagulation playa primary role in determining clinical outcome.
ABSTRACfS
February 1995
data support the concept that hemodynamic shear stresses are important in atherogenesis, and that atherosclerotic plaques at arterial bifurcations are more likely to occur in areas believed to be low rather than high-shear.
Preconditioning and Cardioprotection Wednesday, March 22, 1995, Noon-2:00 p,m. Ernest N. Morial Convention Center, Hall E Presentation Hour: 1:00 p.m.-2:00 p.m. Preconditioning with 15-min Ischemia Extends Myocardial Infarct Size After Subsequent 3Q.min Ischemia In Rabbits
11005-761
Kenzo Yamasaki, Hisayoshi FUjiwara 1, RYOli Yokota, Masami Miyamae, Masaru Tanaka. Shigetake Sasayama. Kyoto University, Kyoto, Japan; 1 Gifu University, Gifu, Japan
Ischemic preconditioning (PC) with 5-min ischemia(l) and reperiusion (R) limits infarct size (IS) after subsequent I in rabbits. The aim of this study was to evaluate whether PC with longer I was also protective. Open chest rabbits underwent 30-min occlusion of coronary artery and 48-hrs R. PC was elicited by either a preceding 5-. 10- or 15-min I followed by 5-min R. Additional group underwent 15-min 1& 48-hrs R. IS was measured histologically and expressed as a percentage of the area at risk (MR).
\1005- 78
1
355A
Myocardial Preconditioning by Laser Irradiation
Peter Whittaker, Robert A. Kloner. Heart Institute. Good. Samaritan Hospital & University of Southern California, Los Angeles, CA We previously demonstrated that transmural laser channels made after coronary occlusion did not acutely enhance blood flow or reduce infarct size. In contrast, other studies (which did not measure blood flow) reported increased survival and/or reduction of necrosis when laser channels were made prior to coronary occlusion. To reconcile this apparent paradox. we speculated that laser channels made prior to occlusion might protect the heart via a mechanism independent of blood flow. To test this hypothesis, we randomized 12 rats to either; (1) control: 1 hour of coronary artery occlusion followed by 5 hours of reperiusion. or 12) laser: 6 non-transmural channels were made in the anterior wall of the left ventricle using a holmium:YAG laser coupled to a 400 micron diameter optic fiber. Two minutes after the last channel was made, the left coronary artery was occluded for 1 hour and then reperiused for 5 hours. We monitored lead I of the ECG and noted the incidence of ventricular tachycardia (VT) and fibrillation (VF). At the end of the protocol. the artery was briefly reoccluded and we determined the area at risk (AR) by injection of pigment into the circulation. Heart slices were incubated in triphenyltetrazolium chloride solution to delineate the area of necrosis (AN). which was expressed as a percent of area at risk (AN/AR). [data given as mean ± SEMI
Control Laser
AR
AN/AR
VTNF
49 ± 3 45 ± 5
61 ± 9 35 ± 4*
5 0*
Group
AAR(OfoLV)
IS (%LV)
IS (OfoAAR)
"'p < 0.03 versus control
non-PC (n ~ 15) 5-min PC (n = 10) 10-min PC (n ~ 10) 15-min PC(n = 15) 15-min I (n = 10)
26.7 ± 2.1 26.7 ± 2.7 28.4 ± 31 25.S ± 1.8 2S.3 ± 3.8
11.1 ± 1.5 3.1 ± 1.0* 3.5 ± OS* 20.1 ± 1.S*#b 5.4 ± 1.0*
40.1 ± 38 10.4 ± 2.9* 11.7 ± 24* 77.4 ± 3.7*#b 18.3 ± 1.0*
Although laser channels were associated with thermally-induced necrosis, total infarct size was smaller in laser-treated hearts. Protection of muscle was most prominent in heart slices containing laser channels. but also occurred in slices without channels. Laser treatment also significantly reduced the incidence of VT and VF. In conclusion. non-transmural laser channels "preconditioned" the heart against subsequent ischemia. Although the mechanism of protection is unknown, it cannot be attributed to increased blood flow to the tissue because the channels did not connect to the ventriCUlar cavity.
*p < 0.05 vs. non-PC, #p < 0.05 vs. 5 min PC, b p < 0.05 vs. 10 min PC Since 15-min I caused infarct (18% of AAR). IS caused by test I per se in 15-min PC group was 59.5 ± 3.7% of AAR (p < 0.05 vs. non PC). Thus, PC with 10-min I is as protective as that with 5-min I. However, PC with 15-min I accelerated myocyte necrosis during subsequent I. Conclusion: We conclude that ischemic duration of PC is a determinant of its cardioprotection, and PC with too long ischemia is not protective but harmful.
11005-771
Is Activation of 5' ·Nucleotidase and Following Adenosine Release a Common Pathway for Mediating Ischemic Preconditioning Among Species?
Kazuo Komamura, Masafumi Kitakaze, Koichi Node. Tetsuo Minamino, Yuji Okuyama. Toshinao Kurihara. Yukihiro Koretsune, Michitoshi Inoue. Masatsugu Hori, Takenobu Kamada. The 1st Dept. of Med., Osaka Univ: School of Med.., Osaka, Japan
There is a rising interest on the subcellular mechanism of cardioprotection afforded by ischemic preconditioning (IP). Adenosine has been reported to playa primary role for preconditioning in dogs, pigs. rabbits but not in rats. Common compounds or mechanisms for preconditioning among species would seem to have some benefits in the clinical settings. In dogs. we reported that an increase in ecto-5'-nucleotidase (5'N) activity is responsible for the infarct size (IS)-1imitation of IP To test the hypothesis that IS-limitation afforded by IP is also attributable to activation of 5'N in rabbits, primary branch of the left coronary artery was occluded for 30 min followed by 3 hrs reperfusion with one time occlusion for 5 min prior to prolonged ischemia in the presence or absence of Ct.p-methyleneadenosine 5'-diphosphate (AOPCP). a specific inhibitor of 5'N. In the absence of AOPCP, IS in the IP group was smaller than that in the control group (17.1 ± 1.9 vs. 29.7 ± 5.2% of risk area. mean ± SE. n = 5 each. p < 0.05). although the risk area was not different in both groups. IP increased 5'N activity in ischemic area compared with that in non-ischemic area (42.1 ± 5.0 vs. 21.2 ± 1.9 nmollmg proteinlmin, p < 0.Q1). When non-hypotensive dose of AOPCP (0.3 mg/kg/min) was infused from the left atrium 15 min before the IP and continued for 60 min after reperfusion. IS-limitation was blunted (IS: 30.2 ± 4.7%). Thus we conclude that increase in 5'-nucleotidase activity is primarily responsible for IS-limitation of IP in rabbits. Activation of 5'-nucleotidase may be a commom pathway for mediating IP both in dogs and rabbits.
Serial 1 H NMR Spectroscopic Detection of Myocardial Lipid Accumulation Following Brief Coronary Ischemia and Elevation of Serum Lipids in Dogs James A. Balschi. David D. Ku, Ingrid Straeter-Knowlen, Jenny Hai, Paul Wolkowicz, William 1. Evanochko, Jan den Hollander, James B. Caulfield, Gerald M. Pohost. Div: of Cardiovascular Disease, Department of Medicine, University of Alabama at Birmingham, AL
We employed a 1H NMR surface coil spectroscopic method to continuously monitor myocardial lipid accumulation following 90-min coronary occlusion and 4 hrs reperiusion in 12 dogs. In the 7 saline-treated control dogs, significant myocardial ischemic damage was noted by both triphenyltetrazolium staining and histologic examination. Slight increases (+ 15.5%) in lipid resonances were also observed during 4-hr reperiusion in the reversibly injured subepicardial ischemic/reperfused myocardium, but not the subendo-cardial infarcted region. Transient elevation of serum lipids in 5 dogs from 18 ± 3 mg/dl to 490 ± 182 mg/dl with a 90-min infusion of Intralipid (1 mllkg bolus followed by 0.025 mllkg/min) during reperiusion further increased the lipid resonances in the reversibly injured subepicardium (+61.8%). The subendocardial infarcted tissues were only minimally affected. Discontinuation of Intralipid infusion with return of serum lipids (36 ± 14 mg/dl) did not reverse the myocardial lipid accumulation. Ex vivo determinations of tissue triglyceride content and histochemical (Oil-Red-O) staining confirmed the preferentiallipid accumulation in the reversibly injured myocytes. Conclusion: Results of the present serial 1H NMR spectroscopic study confirm our earlier findings and further suggest a preferential and temporal accumulation of lipids in the ischemically jeopardized myocardium. Increases in serum lipid levels could exacerbate their accumulation in the ischemic myocardium.
11005-80
I
Evidence That A 3 -Receptor Activation Contributes to Preconditioning-induced Cardioprotection In Ischemic Cardiac Myocytes
Jianxun Wang, Lisa Drake, Kevin Mullane, David Bullough. Cardiovascular Research. Gensia Inc., San Diego, CA
Ischemic preconditioning (PC) reduces post-iSChemic myocardial injury by an adenosine-mediated mechanism. This study evaluated the adenosine receptors involved in protecting ischemic cardiac myocytes. Ischemic injury was simulated by exposure of the myocytes (paced at 1 Hz) to ischemic buffer
356A
ABSTRACTS
lACC
containing (mM) 2'-deoxyglucose (20), NaCN (1). Na-lactate (20). K+ (10) at pH o 6.6 (3rC). Changes of myocyte length were monitored with an opticalvideo edge recording system, and hypercontracture was used as the index of irreversible cell injury (cell death). Results: PC (2 min ischemia followed by 15 min reperfusion) significantly reduced cell injury resulting from the subsequentextended ischemia (10 min) and reperfusion (15 min), as indicated bya reduction in cell death from 67 ± 6% (cells ~ 110, control) to 29 ± 5% (cells = 101, with PC, p < 0.001). PC-induced cardioprotection was only partially blocked by the maximally effective dose of the adenosine A, -receptor antagonist DPCPX (1 00 nM) Icell death = 43 ± 3%, cells = 88, P < 0.05 vs control) but completely blocked by either the combination of DPCPX (100 nM) with the adenosine A3-receptor antagonist BW A1433 (1 /LM) (cell death ~ 64 ± 4%; cells = 82; P = NS vs control). or the non-selective adenosine receptor antagonist, 8-SPT (100 /LM) (cell death = 59 ± 5%; cells ~ 86; P = NS vs control). as shown in the Figure. Conclusion: PC-induced cardioprotection is mediated in part through the activation of adenosine A3-receptors.
.-.
80
-
60
C .r: ca GI
•ora
40
"i
20
EJ
o
11005-81 1
Fe PC+OPCPX
~ PC+OPCPX
."
o
control
+ BW A1433 PC+ 8-SPT
Myocardial Protection by Na +IH + Exchange Inhibition in Ischemic, Reperfused Porcine Hearts
Hermann H. Klein, Sibylle Pich, Rainer M. Bohle, Jutta Wollenweber, Klaus Nebendahl. Universities of Marburg and G6ttingen, Fed. Rep. of Germany The protective effect of the Na+/H+ exchange inhibitor HOE 694 was tested in porcine hearts subjected to 45 min of regional ischemia and 24 h of reperfusion. The compound (3 mg/kg) was intravenously injected in 6 pigs each either 10 min before ischemia (group A) or 10 min before reperfusion (group B). Six animals served as controls. Apart from the main end-points, infarct size and regional systolic shortening, the effect of HOE 694 on global hemodynamic parameters which included coronary blood flow and coronary venous oxygen saturation was evaluated. Although the Na+ IH+ exchange inhibitor did not affect global hemodynamics, preischemic treatment with HOE 694 decreased infarct size from 65 ± 18% (control group) to 12 ± 9% (p < 0.01) and improved systolic shortening from 8 ± 6% (control group) to 28 ± 9% P < 0.02). In addition, increase in heart rate and myocardial contracture during early reperfusion were significantly attenuated in group A. Treatment of group B did not exhibit protective effects. Conclusion: Na+/H+ exchange inhibition is a very protective means in myocardial ischemia and reperfusion when administered before ischemia. In this model, it was ineffective when given before reperfusion.
110061
February 1995
Counteracting Thrombin and Lipids in Acute Coronary Syndromes
Wednesday, March 22, 1995, Noon-2:00 p.m. Ernest N. Morial Convention Center, Hall E Presentation Hour: Noon-1 :00 p.m. 11006-41
I
Effect of Previous Treatment with Aspirin or Nitrates on the Clinical Manifestation of Acute Coronary Syndrome
David Garcia-Dorado, Juan Oliveras, Pilar Tornos, Gaieta Permanyer, Antonia Sam bola, Maite Santos, Pierre Theroux, J. Soler-Soler. Hospital Vall d'Hebron, Barcelona, Spain; Montreal Heart Institute, Canada
Aspirin (ASA) and nitrates inhibit platelet aggregation by different mechanisms, and it has been suggested that their antiaggregating effects could be additive. To analyze the influence of previous treatment with aspirin (ASA) or nitrates on the clinical manifestations of acute coronary syndrome, a series of 323 pts consecutively admitted to the cardiology emergency room with unstable angina (UA) or acute myocardial infarction (MI). and with a previous history of coronary heart disease, was prospectively characterized. A standardized questionnaire was used to determine risk factors, previous cardiac history, and use of drugs preceding the index event. Previous use was defined as any dose of ASA during the week before, or of oral or transdermal nitrates during the 24 h before the onset of the event. The final diagnosis by serial ECGs and enzyme determinations, was UA in 226 pts, and MI in 95. Fifty-one pts had received previous treatment with ASA but not with nitrates, 51 had received nitrates but not ASA, 105 had received both drugs and 94 had received neither ASA nor nitrates. The final diagnosis was MI in 12 (24%) pts who had received ASA, 12 (24%) in pts who had received nitrates, 21 (20%) in pts on both ASA and nitrates, and 43 (46%) in those receiving neither ASA nor nitrates (p ~ 0.0003). Multiple logistic regression analysis identified prior ASA and prior nitrates, but not age, sex, risk factors, previous myocardial infarction, or prior treatment with beta blockers or Ca++ entry blockers, as independent predictors of UA vs MI. The regression model did not detect any interaction between ASA and nitrates. These results suggest that both prior treatment with ASA and with nitrates modify the clinical manifestations of acute ischemic syndrome reducing its severity, and that these effects are compatible with their effects being additive.
11006-421
What Beyond Aspirin and Anticoagulation Improves Outcome in Unstable Angina? Effect of Medical Therapy
Steven Borzak, Phillip L. Kraft, Lori Douthat, Christopher P. Cannon, Elliott Antman, Joe Massaro, Sebastian 1. Palmeri, Judith S. Hochman, Carolyn 1. McCabe, Joanna Fuchs, Burt Adelman, TIMI-7 Investigators. Henry Ford Hospital, Detroit, MI; Brigham and Women's Hospital, Boston, MA
11005-821
Myocardial and Coronary Vascular Protection After Coronary Occlusion and Reperfusion by Selective Sinoatrial Node Inhibition
Roger Williams, Wilmer W. Nichols, Liying Chen, Michael S. Stalvey, Linda V. Thompson, Tiffany D. Boyd, Jawahar L. Mehta, Carl J. Pepine. University of Florida and VA Medical Cente" Gainesville, FL
Improved regional myocardial function and abnormal flow reserve resulting from myocardial ischemic injury has been observed with ,II-blockade. To determine if heart rate reduction alone would offer similar protection, anesthetized dogs were subjected to left anterior descending (LAD) occlusion and given a selective SA node inhibitor (ZD7288 0.5 mg/kg, n = 5 or buffer, n = 7). After 1 hour of occlusion they were reperfused. ZD7288 decreased heart rate by 28 ± 2% (153 ± 14 to 120 ± 11 bpm, p < 0.05) at 1 hr after reperfusion. In buffer-treated dogs, peak reactive hyperemic (RH) response after 20 sec LAD occlusion, (index of coronary flow reserve). fell from 276 ± 22% to 135 ± 18% and LAD regional shortening fraction (SF, by ultrasonic crystals) decreased from 9.7 ± 1.5% to 0.6 ± 0.1 % after reperfusion (both, p < 0.001). In ZD7288-treated dogs, peak RH and SF after reperfusion (227 ± 19% and 4.2 ± 0.8%, respectively) were preserved (p < 0.05) vs buffertreated dogs. Despite similar area of left ventricular (LV) at risk, infarct area (as % of LV). was also smaller in ZD7288-treated vs. buffer-treated dogs (14.0 ± 0.5 vs 23.0 ± 1.10%, P < 0.05). Heart rate was maintained constant with atrial pacing in five other ZD7288-treated dogs and neither peak RH or SF were preserved compared with buffer-treated dogs. Thus, selective SA node inhibition alone, induced after coronary occlusion, results in myocardial and coronary vascular protection after reperfusion. Selective SA node inhibition may have clinical utility in acute myocardial patients who are not candidates for beta blockers.
Medical treatment consisting of beta-blockers (BB), calcium blockers (CB) and nitrates (N) is recommended and frequently employed in patients (pts) before and during hospitalization with unstable coronary syndromes (UA). but the benefit is unclear in the setting of combined aspirin and anticoagulation. To study the effect of each of these drugs on in-hospital events, we examined 410 pts with UA entered in the TIMI-7 trial in which all pts received aspirin and one of 4 doses of the direct thrombin inhibitor, hirulog. Prior to hospitalization, 44% of pts received BB, 50% CB, and 51 % N. Compared to pts not on these drugs, pts on each medication were older (average 62 vs 59 yrs). had a higher incidence of prior MI(BB, CB, N), revascularization (CB, N), hypertension (BB, CB, N). and diabetes (CB, N), and were more likely to be receiving aspirin IBB, CB, N). Stepwise regression showed that prior treatment with any of the 3 drugs was not predictive of in-hospital death, MI or documented recurrent ischemia. After enrollment and during hospitalization, 71 % of pts received BB, 66% CB, and 95% N at the discretion of their physicians. The in-hospital occurrence of death (4%). Ml (6%), recurrent ischemia (8%) or their combined incidence (14%), the number or severity of in-hospital anginal episodes, or the incidence of catheterization (64%) or revascularization (38%) were not significantly related to treatment with any of the 3 drugs. The combined incidence of in-hospital death, MI or recurrent ischemia was best predicted by the presence of ECG changes on admission (multivariate adjusted odds ratio [OR] 2.83, p < 0.01) and advanced age (OR 2.38, P < 0.01) but not by other factors. Prior or newly instituted anti-ischemic medical therapy, administered in a nonrandomized fashion in this trial, may have contributed to clinical stability. During hospitalization for UA, aspirin and anticoagulation playa primary role in determining clinical outcome.